Regulation of many immune response genes depend on a 10 bp DNA sequence termed kappaB. This sequence is bound by a family of protein factors related to the Rel oncogene. The prototype transcription complex binding to the sequence, termed NF-kappaB, has been conventionally defined as a heterodimer between a P50 DNA binding protein and a P65 (RelA) activation protein that is typically sequestered in the cytoplasm by a protein called I-kappaB. Following certain types of stimulation to the cell, a specific protein kinase complex called I-kappaB kinase causes the phosphorylation of I-kappaB followed by its ubiquitination and degradation. Among the stimuli that can release NF-kappaB is the triggering of the T cell receptor (TCR) or B cell receptor (BCR) by antigen during an immune response. However, this transcription factor plays a role in the induction of diverse sets of genes throughout the body in response to hundreds of different inducers. While studying a rare clinical condition of immunodeficiency, We have also discovered the first germline mutation in CARD11, a protein that forms a vital signaling link between the antigen receptor in both B and T lymphocytes, in one family with congenital lymphoid hyperplasia first reported in The New England Journal of Medicine in 1971 as well as in a child adopted from China in a second family. The affected family members exhibit excessive accumulation and defective differentiation of B lymphocytes but not T lymphocytes. The dominant missense mutations identified will constitutively activate NF-kappaB in both B and T cells contributing to downstream proliferation in B cells. However,it causes apparent non-responsivenes or anergy in T cells resulting in poor IL-2 production and proliferation. Thus, we have identified the underlying genetic cause of this hereditary B cell disorder and have uncovered a potential molecular explanation for why CARD11 mutations may predispose to B but not T lymphoid malignancies. This can be understood in terms of the 2 signal model in which T lymphocytes require antigen receptor(signal 1) as well as costimulatory (signal 2)both required for T cell proliferation, whereas the provision solely of signal 1 leads to poor responsiveness or anergy. We observed this phenomenon in our patients, since E127G CARD11 causes internal constitutive activation of NF-kappaB, an important feature component of signal 1, in the absence of a concomitant signal 2. In contrast, B cell proliferation can be triggered by BCR crosslinking alone, which is mimicked by mutant CARD11-driven NF-kappaB activity. We posit that a chronic TCR-like signal 1 provided through mutant CARD11 can be converted to a proliferative signal for the patients T cells in vivo when proper costimulation (signal 2) is provided by professional antigen presenting cells. Defects in T cell help to B cells, related to T cell hyporesponsiveness, may partly explain the paucity of germinal centers and autoimmune manifestations in these patients. On the other hand, deficiencies in T cell-independent humoral responses to polysaccharide antigens also point to intrinsic defects in B cell signaling and effector function with E127G CARD11 present. Our discovery of a germline gain-of-function mutation in CARD11 illuminates how antigen receptor signaling is regulated differently in B and T cells, even though the proximal signaling machinery is nearly identical. This surprising difference has not been revealed by somatic CARD11 mutations in diffuse large cell B cell lymphoma, in which only B cells harbor the mutation and can potentially explain the preponderance of B cell rather than T-cell lymphomas associated with activating mutations in this gene. Our molecular analysis of this autosomal dominant lymphoproliferative disorder, which may represent a novel precursor state for B cell malignancies like B-chronic lymphocytic leukemia, reveals how selective dysregulation of NF-kappaB via CARD11 may predispose to selective proliferation and differentiation arrest in B cells, but defective proliferation and function of T cells. By re-examining the molecular basis of a rare genetic disorder first reported for decades ago, our discovery may open new avenues to treat this lymphoproliferative disease and prevent development of lymphoma by agents that can block NF-kB.